Subclinical hypothyroidism (SCH) is defined as an elevated serum thyroid-stimulating hormone level with a normal total and free thyroxine (T4) level. There is a certain degree of debate regarding the risks associated with this condition and whether treatment is beneficial. Individuals with SCH are either asymptomatic or present with milder symptoms than those with overt hypothyroidism. Although SCH does not cause significant clinical abnormalities, there are certain long-term consequences which have been documented. The diagnosis is based purely on biochemical investigations. Treatment of this condition is not indicated in all cases since thyroid function tests tend to normalize in 6%–35% of patients. However, there are specific clinical indications for treatment and oral levothyroxine is the treatment of choice in such situations.

A 29-year-old female, married for 5 years, was referred for the evaluation of primary infertility. She had normal menstrual cycles. She had progressive weight gain and tiredness but with no classical symptoms of hypothyroidism. The BMI of the patient was 28 kg/m2. On examination, she had acanthosis nigricans; her blood pressure was 130/80 mmHg and ankle jerks were normally elicited. A diffusely palpable goiter with rubbery consistency was palpable. Biochemical evaluation revealed normal parameters except for a high serum thyroid-stimulating hormone level of 9 µIU/ml (reference interval – 0.3–4.5) and a low total thyroxine (T4) level of 7.5 µg/dl (reference interval – 4.5–12.5) with normal free thyroxine levels too. Antithyroglobulin and antithyroid peroxidase antibody titers were >100 units confirming the diagnosis of Hashimoto’s thyroiditis. What is the next line of management?

Introduction

Subclinical hypothyroidism (SCH) is defined as an elevated serum thyroid-stimulating hormone (TSH) level with a normal total and free thyroxine (FT4) level. The prevalence of SCH in large epidemiologic studies, namely, Framingham, Rotterdam, and Colorado studies are 8.9, 10.3, and 9.5%, respectively.[1],[2],[3] SCH is more prevalent in relatively iodine-rich areas; 6.1% to 18.0% compared to 0.9% to 3.8% in iodine-deficient areas.[4] The risk of progression of SCH to overt hypothyroidism is estimated to be approximately 2%–6% per year; the risk factors for the same are female gender, persons with higher TSH levels, those with higher levels of thyroid antibodies, and those with low-normal FT4 levels.[5]

Set Point of Thyroid-Stimulating Hormone

Serum TSH and FT4 show substantial variability among healthy individuals, whereas the range of variability within the healthy person tends to be relatively narrow. This finding suggests a unique set point of the hypothalamic–pituitary–thyroid axis for each person and explains why a TSH of 10 mIU/l is associated with a normal FT4 level in some individuals and a decreased FT4 level in others.

Elderly individuals, women, and those with antithyroid antibodies have a stronger log-linear relationship between TSH and FT4 levels than the young men, and those with lower levels of antithyroid antibodies.[6]

Symptoms

Many patients with SCH are asymptomatic. However, there is evidence to suggest that a certain subgroup of patients tend to report symptoms of overt hypothyroidism more often than age-matched controls. These symptoms are usually milder than those in patients with overt hypothyroidism and tend to increase in both number and severity with higher TSH levels.

Long-Term Clinical Consequences

Although SCH does not cause significant clinical abnormalities, there are certain long-term consequences which have been documented in prospective studies of those patients.

SCH is found to be associated with an increased total cholesterol levels and low-density lipoprotein cholesterol levels and with subclinical measures of cardiovascular disease.[7] However, there is no clear evidence for these associations.

Higher TSH levels are associated with increased body-mass index and increased waist circumference. Elevated levels of leptin, found in obese patients, are another potential cause for high TSH in patients with obesity. Leptin is shown to stimulate centrally the transcription of pro-thyrotropin-releasing hormone (TRH) and consequently TSH. In addition, leptin also enhances the activity of deiodinases. Moreover, adipose tissue secretes inflammatory cytokines such as tumor necrosis factor alpha, interleukin (IL)-1, and IL-6, which inhibit sodium/iodide symporter mRNA expression and iodide uptake in the follicular cells of the thyroid gland.[8] The elevated TSH level of obese patients was found to normalize following weight loss with either bariatric surgery or by instituting a hypocaloric diet.[9]

The risks of female infertility, spontaneous abortion, and other complications associated with pregnancy, such as gestational hypertension and preeclampsia, are found to be increased in women with SCH and associated with positive antithyroid antibodies. During pregnancy, various changes may occur in thyroid homeostasis, including an increased demand for thyroid hormone, which is mediated by high levels of human chorionic gonadotropin. Hence, TSH may increase in patients with preexisting mild thyroid dysfunction.[10]

Diagnosis

SCH is purely a biochemical diagnosis that is defined as an elevated serum TSH level and a normal FT4 level. Since multiple factors, such as subacute thyroiditis, recovery from nonthyroidal illness, and medications (e.g., amiodarone and lithium), can cause transient abnormalities in the serum TSH level, a transient increase in the TSH level should be ruled out before a diagnosis of SCH is made. All these patients should have a repeat measurement of TSH and FT4 after a 2-to-3-month interval, along with antithyroid antibodies. The presence of antithyroid antibodies supports the diagnosis of an autoimmune cause of SCH, and these patients have an increased chance of progression to overt hypothyroidism that may be twice compared to those with a negative test for antithyroid antibodies (cumulative incidence at 9 years, 59% vs. 23%).[11] However, a repeat measurement of serum of antithyroid antibodies is not recommended in the management of SCH.[12] Although ultrasonography of the thyroid gland provides an increased vascularity to suggest thyroid autoimmunity, ultrasonography is not routinely recommended.

Indications for Treatment

In patients who are incidentally detected to have SCH, the thyroid functions may normalize in 6%–35% of patients. If thin-film transistor (TFT) normalize, then there is no need to do further tests, especially if the patients are asymptomatic or have no goiter and anti-TPO antibodies are not positive. But if SCH is persistent, then TFT should be tested every 6 months for the first 2 years and then annually thereafter.[13]

However, there are specific clinical situations where it better to initiate treatment. The indications for treatment are listed in [Table 1].

Oral levothyroxine is the treatment of choice in SCH if there is a clinical indication. The current evidence does not suggest the use of either liothyronine (T3) or combined levothyroxine/liothyronine treatment for SCH. The ETA guidelines recommend a weight-adjusted starting dose of 1.5 μg/kg for patients without cardiac disease and at a lower dose with gradual increase in the dose every week for patients having heart problems and in the elderly.[14] The serum TSH should be rechecked 2–3 months after the initiation of levothyroxine, with the aim of maintaining the TSH in the lower half of recommended range (0.4–2.5 mIU/l and a higher range (1.0–5.0 mIU/l) for elderly patients (>70 years).

There is a risk of overtreatment of this condition in up to 14%–21% of patients. This may present with symptoms of nervousness, palpitations, worsening of ischemic heart disease and heart failure, atrial fibrillation, and decreased bone mineral density with an increased fracture risk.

Coming to the patient discussed in the case scenario, in view of the pregnancy plan and positive antithyroid antibody, she was started on oral thyroxine 50 mcg/day and was advised to keep the level of TSH within normal limits before pregnancy.

Conclusion

SCH is a topic of debate with regard to the risks that may be associated with this condition and whether treatment may be beneficial in these patients. The balance of risk and benefit is influenced by the degree of TSH elevation, associated risk factors, and comorbid conditions.